People who live and work in cold areas have an increased prevalence of hypertension and related cardiovascular diseases (e.g. stroke and myocardial infarction). The greatest mortality and morbidity due to cardiovascular diseases occur in the cold winter season. Cold temperatures increase the severity of hypertension in hypertensive patients. Therefore, studies regarding the pathogenesis of cold-induced hypertension (CIH) are strongly indicated. Our long-term goal is to understand the role of cold temperatures as a factor in cardiovascular disease for developing preventive and therapeutic strategies. Rats intermittently exposed to cold (5[unreadable]C; 41[unreadable]F) develop hypertension, including cardiac hypertrophy, within three weeks of exposure. Presently this is the only "natural" form of experimentally-induced hypertension, requiring no surgery, drugs, hormones or genetic manipulation. Our central hypothesis, based on our strong preliminary data, is that intermittent cold exposure activates the endothelin (ET) system and that the ET activation plays a role in the development and maintenance of CIH. The objective of this proposal is to determine the effects of intermittent cold exposure on the ET system and to assess its potential contribution to CIH. The proposed research is centered on four Specific Aims: 1) To determine the effect of intermittent exposure to cold on the expression of preproendothelin-1 and ET-converting enzyme and the production of endothelin-1 (ET- 1); 2) To determine the effect of intermittent cold exposure on the regulation of ETA, ETBi and ETB2 receptor expression; 3) To determine the effect of chronic blockade of ETA, ETBi and ETA+B receptors on CIH and cardiac and vascular hypertrophy; 4) To evaluate the role of cardiac ATi receptors in the cold-induced increase in cardiac ET production and the role of cardiac mineralocorticoid receptor (MR) in the cold-induced regulation of cardiac ETA/ETB2 receptors. We are uniquely positioned to undertake the proposed research because the CIH/rat model was originally developed in our laboratory. The proposed work will use the state-of-the-art techniques to evaluate, for the first time, the potential role of the ET system in CIH, a novel model of hypertension. The results will reveal new insights into prevention and will allow optimization of therapeutic approaches for cold-related cardiovascular diseases, which is important for people who live in cold areas, for people who have outside duties in winter, and for people who work daily in artificial cold environment.